Inhibition of Aminoglycoside 6′-<i>N</i>-Acetyltransferase Type Ib-Mediated Amikacin Resistance in Multidrug- and Carbapenem-Resistant Clinical Strains by Cadmium in Combination with Pyrithione
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The ongoing antibiotic resistance crisis is among the most pressing public health chal-lenges. The rise and dissemination of multidrug-resistant bacterial pathogens is reaching the point when some become untreatable. Consequently, besides discovering novel antibiotics, alternative strategies must be explored to manage the problem. One of them is the development of inhibitors that can overcome resistance to antibiotics currently in use. Resistance to aminoglycosides such as amikacin is mainly due to the action of aminoglycoside modifying enzymes. Despite being refractory to most resistance en-zymes, the semisynthetic amikacin is inactivated by the action of aminoglycoside 6’-N-acetyltransferases type I [AAC(6')-I], of which AAC(6')-Ib is the most common in Gram-negative pathogens. The recent discovery that certain divalent and monovalent cations can interfere with enzymatic acetylation catalyzed by AAC(6')-Ib has opened up new possibilities for developing formulations that combine antibiotics with these cations to enhance their efficacy. Addition of CdCl2 to in vitro enzymatic assays inhibited the transfer of an acetyl group to the 6'-N position of amikacin, kanamycin, and tobramycin. This result demonstrated the potential of Cd2+ as an adjuvant to aminoglycosides that can become effective for treating infections resistant due to AAC(6')-Ib. It was initially dis-appointing that, as with other divalent cations, addition of CdCl2 to cultures of bacteria harboring AAC(6')-Ib did not reverse resistance. However, the inhibitory action of Cd2+ became evident when it was added to cultures in complex with the ionophore pyrithione. The complex efficiently inhibited resistance in Acinetobacter baumannii and Klebsiella pneumoniae harboring AAC(6')-Ib. Furthermore, the combination efficiently inhibited amikacin resistance in carbapenem-resistant K. pneumoniae clinical isolates. These results add another cation to the arsenal of potential adjuvants for aminoglycosides, which could be developed either alone or in coordination complexes with ionophores to treat multi-drug-resistant infections.